© 2014 Macmillan Publishers Limited. All rights reserved. The TRIM37 (also known as MUL) gene is located in the 17q23 chromosomal region,which isamplified inupto 40%of breast cancers1. TRIM37 contains a RINGfinger domain, a hallmark of E3 ubiquitin ligases2, but its protein substrate(s) is unknown. Here we report that TRIM37 mono-ubiquitinates histoneH2A, a chromatinmodification associated with transcriptional repression3. We find that in human breast cancer cell lines containing amplified 17q23,TRIM37 is upregulated and, reciprocally, the majorH2Aubiquitin ligase RNF2 (also known as RING1B)3,4 is downregulated. Genome-wide chromatin immunoprecipitation (ChIP)-chip experiments in 17q23-amplified breast cancer cells identifiedmany genes, includingmultiple tumour suppressors,whose promoters were bound byTRIM37 and enriched for ubiquitinated H2A. However, unlike RNF2, which is a subunit of polycomb repressive complex 1 (PRC1)3-5, we find that TRIM37 associates with polycomb repressive complex 2 (PRC2). TRIM37, PRC2 and PRC1 are co-bound to specific target genes, resulting in their transcriptional silencing. RNA-interference-mediated knockdown of TRIM37 results in loss of ubiquitinated H2A, dissociation ofPRC1 andPRC2fromtarget promoters, and transcriptional reactivation of silenced genes. Knockdown of TRIM37 in human breast cancer cells containing amplified 17q23 substantiallydecreases tumour growth inmouse xenografts. Conversely, ectopic expression of TRIM37 renders non-transformedcells tumorigenic.Collectively, our results reveal TRIM37 as an oncogenic H2A ubiquitin ligase that is overexpressed in a subset of breast cancers and promotes transformation by facilitating silencing of tumour suppressors and other genes.